# WFS1 Wolframin — K705N Variant Card

**Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill**

*Lysine → Asparagine at position 705 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.990 (near-maximum), DynaMut2 ΔΔG -0.66 kcal/mol (destabilising). A charge-loss variant in the high-confidence lumenal fold.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | K705N (p.Lysine705Asparagine) |
| **DNA change** | c.2115G>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003637013 |
| **Amino acid change** | Lysine (K) → Asparagine (N) — a positively-charged primary-amine-bearing residue replaced by a smaller polar amide. Loss of positive charge and reduced side-chain length, but H-bonding capacity preserved. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 705** | **90.00** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 705 sits in the ER lumen in a well-folded region (pLDDT 90). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position 705 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places K705 within 5 Å of TYR706 (2.4 Å), PHE704 (2.5 Å), THR778 (3.6 Å, a longer-range contact across the lumenal fold), GLN819 (4.4 Å, another distal contact), and ARG703 (4.5 Å). The neighbors are aromatic-rich (Y706, F704), polar (T778, Q819), and basic (R703, K705 itself).

The wild-type lysine at 705 carries a positive charge that likely participates in a salt-bridge or hydrogen-bonding network with the nearby threonine (T778) and glutamine (Q819) residues — both H-bond acceptors. The lysine side chain is long enough (4-carbon alkyl + amine) to reach across to these distal positions, contributing to a folded geometry that brings sequence-distant residues into proximity.

Replacing lysine with asparagine removes the positive charge and shortens the side chain. The polar amide of asparagine can still hydrogen-bond, but it can no longer reach the same distal positions as the lysine's longer chain. The local fold geometry that depends on the K705-T778 or K705-Q819 contact is perturbed.

DynaMut2's |ΔΔG| of 0.66 reflects the modest energetic cost of the fold rearrangement. AlphaMissense's 0.990 score captures the severity of the lost functional contact.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9895** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.66 (Destabilising)** |
| Job ID | 177990252901 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990252901 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/08/16 00:00 |
| Inheritance | Inheritance not specified. ClinVar Pathogenic classification establishes clinical relevance. |
| WFS1 variant landscape | K705N is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for K705N — ClinVar Pathogenic by review evidence)

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## Research Path Decision Tree

```
ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking
```

## Final Schema Categorization

**Category 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.66 kcal/mol — fold survives. AlphaMissense 0.990 confirms severe functional consequence.<br/><br/>The mechanism is loss of a long-range electrostatic/H-bond contact (K705 to T778 or Q819) that the wild-type residue's extended side chain made. Therapeutic strategy: site-directed small molecules that bridge the K705-T778-Q819 microregion, restoring the long-range contact the wild-type lysine provided.<br/><br/>This is a good example of how the Atlas's PDB neighbor analysis surfaces distal contacts that sequence-based analysis would miss. T778 is 73 residues away from K705 in sequence but only 3.6 Å away in structure.

**Why this card matters.** K705N's mechanism — loss of long-range structural contact via a long-side-chain residue — is one the Atlas captures well through its 5 Å neighbor extraction. The wild-type lysine reaches across the folded domain to contact residues 73 sequence positions away. Drug discovery here targets the cross-domain contact rather than the local position alone.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `K705N_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 705 with ball-and-stick + neighbors within 5Å)
- `K705N_variant_card.md` — this card (source of truth)
- `K705N_variant_card.html` — styled printable card
- `K705N_dynamut2_summary.html` — clean offline DynaMut2 result card
- `dynamut2_result.json` — structured result data
- `dynamut2_result_page.html` — local snapshot of the Biosig result page (asset URLs absolutized)
- `K705N_wildtype_interactions.pse` / `K705N_mutant_interactions.pse` — PyMOL sessions

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*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*